The purpose of this study is to is to determine the effects (good and bad) of Zanubrutinib in Combination with Pola-R-CHP and High-dose Methotrexate in patients with Secondary Central Nervous System (CNS) Lymphoma.

Inclusion Criteria:

1. Men and women ≥ 18 years of age on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place).

2. Patients must have histologic confirmation of large B-cell lymphoma (LBCL) defined by the World Health Organization (WHO) classification. All LBCL subtypes are acceptable. Note: Patients with prior treatment for indolent lymphoma are still eligible for participation as long as they did not receive anthracycline-based therapy.

3. Baseline 18-fluorodeoxyglucose (FDG)-positron emission tomography scan/computed tomography (PET/CT) must demonstrate FDG avid lesions compatible with CT-defined anatomical tumor sites (Note: FDG-PET/CT is not mandatory, and patients with CT scans only will be eligible for study entry as well). Patients should have at least 1 measurable site of disease per Lugano classification in FDG-PET/CT or CT scans.

4. Presence of systemic and CNS involvement (brain, cerebellum, brainstem, meninges, cranial nerves, eyes, spinal cord, or a combination of these) at presentation.

5. Determination of CNS involvement can be by brain biopsy, cerebrospinal fluid (CSF) evaluation by cytology and/or flow cytometry, neuroimaging, or strong clinical suspicion by Investigator for which CNS targeted therapy is recommended (ie, numb chin syndrome in patients with high CNS involvement risk).

6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2, except due to lymphoma involvement.

7. Life expectancy of greater than ≥ 3 months.

8. Women should avoid becoming pregnant while taking zanubrutinib and for up to 90 days after ending treatment. Therefore, women of childbearing potential must use highly effective contraceptive measures while taking zanubrutininb and for up to 90 days after stopping treatment. It is currently unknown whether zanubrutinib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method. Pregnancy testing is recommended for women of reproductive potential prior to initiating therapy.

   Agreement to use contraception during study participation.

   1. Female patients of childbearing potential must use highly effective methods of contraception. Recommended acceptable contraception methods are included in Section 5.12.
   2. Patients using hormonal contraceptives (eg, birth control pills or devices) must use a barrier method of contraception (eg, condoms) as well.
   3. A woman is considered of childbearing potential, ie, fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
   4. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause.

9. Male patients with a female partner of childbearing potential are eligible if they abstained, are vasectomized or if they agree to the use of barrier contraception with other methods described above during the study treatment period and for 90 days after the last dose of zanubrutinib.

10. Patients must have normal organ and marrow function as defined below:

    1. Absolute neutrophil count (ANC) > 1,000 cells/mm3 independent of growth factor support within 7 days of study entry (≥ 750 cells/mm3 if lymphoma involvement of the bone marrow or spleen).
    2. Platelets ≥ 75,000 platelets/mm3 independent of transfusion support within 7 days of study entry (≥ 50,000/mm3 independent of transfusion support within 7 days of study entry if lymphoma involvement of the bone marrow or spleen).
    3. Hemoglobin > 9 g/dL or > 8 g/dL in case of bone marrow involvement by lymphoma independent of transfusion support within 7 days of study entry.
    4. Serum total bilirubin ≤ 2 x upper limit of normal (ULN; except patients with Gilberts syndrome).
    5. Aspartate aminotransferase (AST; serum glutamic-oxaloacetic transaminase (SGOT)) and alanine transaminase (ALT); serum glutamic-pyruvic transaminase (SGPT)) ≤2.5 x institutional ULN (≤3x institutional ULN if lymphoma involvement of the liver).
    6. Creatinine within normal institutional limits, or creatinine clearance ≥ 40 mL/min (as estimated by the Cockcroft-Gault equation or alternative formula according to institutional guidelines) for patients with creatinine levels above institutional normal.

11. Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments (SoA).

Exclusion Criteria:

1. Primary CNS lymphoma without evidence of systemic lymphoma.

2. Prior systemic lymphoma therapy (Note: 1 cycle of an anthracycline based regimen, such as rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (R-CHOP), polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP), dose-adjusted etoposide phosphate, prednisone, oncovin, cyclophosphamide, hydroxydaunorubicin, and rituximab (EPOCH-R), or rituximab, cyclophosphamide, vincristine, doxorubicin, and methotrexate (R-Codox-M), and/or 1 dose of intrathecal therapy, will be allowed before enrollment [Section 5.9]). Note: Patients with prior treatment for indolent lymphoma are still eligible for participation as long as they did not receive anthracycline-based therapy.

3. Any uncontrolled or clinically significant cardiovascular disease including the following:

   1. Myocardial infarction within 6 months before screening;
   2. Unstable angina within 3 months before screening;
   3. New York Heart Association class III or IV congestive heart failure;
   4. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes).
   5. Uncontrolled hypertension as indicated by ≥ 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg and/or diastolic blood pressure > 105 mm Hg at screening.
   6. QT interval corrected with Fridericia's formula (QTcF) > 450 msec or other significant electrocardiogram (EKG) abnormalities, including second-degree atrioventricular block Type II or third-degree atrioventricular block.

4. Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura).

5. Uncontrolled intercurrent illness such as liver cirrhosis, autoimmune disorder requiring immunosuppression or long-term corticosteroids (> 10 mg daily prednisone equivalent), or any other serious medical condition, laboratory abnormality, or psychiatric illness which would compromise ability to comply with study procedures.

6. Severe or debilitating pulmonary disease.

7. Concurrent malignancy requiring active therapy.

8. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer.

9. Active fungal, bacterial and/or viral infection requiring systemic therapy.

10. Breastfeeding or pregnant women.

11. Known active infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows:

    1. Patients with positive HIV test and undetectable viral load will be eligible for this study.
    2. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20 IU), and if they are willing to undergo monitoring every 4 weeks for HBV reactivation.
    3. Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable. For more information regarding hepatitis B and C testing, please refer to Section 9.2.5.4.

12. Patients with impaired decision-making capacity.

13. Ongoing treatment with medications that are strong cytochrome P450 (CYP), family 3, subfamily A (CYP3A) inducers.

14. Underlying medical conditions that, in the Investigator's opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs.

15. Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome, stomach or small bowel resection, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

16. History of severe bleeding disorder, such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention.

17. History of stroke or intracranial hemorrhage within 180 days before the first dose of zanubrutinib.

18. Major surgery within 4 weeks of the first dose of zanubrutinib. Major surgery is defined as open-heart, reconstructive, transplant, removal of a brain tumor or a damaged kidney surgery.

19. The patient requires treatment with warfarin, warfarin derivatives, or other vitamin K antagonists.

20. Vaccination or requirement for vaccination with a live vaccine within 28 days prior to the first dose of study drug or at any time during planned study treatment.

21. Hypersensitivity to zanubrutinib, any components of pola-R-CHP, regimen, and/or high-dose (HD) methotrexate (MTX), or any of the other ingredients of the applicable study medications.

22. Concurrent participation in another therapeutic clinical trial.